U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C21H20N4O3
Molecular Weight 376.4085
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ENTINOSTAT

SMILES

NC1=CC=CC=C1NC(=O)C2=CC=C(CNC(=O)OCC3=CN=CC=C3)C=C2

InChI

InChIKey=INVTYAOGFAGBOE-UHFFFAOYSA-N
InChI=1S/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)

HIDE SMILES / InChI

Molecular Formula C21H20N4O3
Molecular Weight 376.4085
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17383217 https://www.ncbi.nlm.nih.gov/pubmed/21888556 https://www.ncbi.nlm.nih.gov/pubmed/12975486

Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.

CNS Activity

Curator's Comment: Entinostat (MS-275) is a potent brain region-selective HDAC inhibitor in mice. https://www.ncbi.nlm.nih.gov/pubmed/16432198 Other study demostartes poor Entinostat (MS-275) brain penetration in non-human primates and rodents. https://www.ncbi.nlm.nih.gov/pubmed/20657706 No human data reported to date.

Originator

Curator's Comment: # Nihon Schering; Pfizer; University of Tokyo

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.3 µM [IC50]
8.0 µM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway.
2007
Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate.
2007 Aug
Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models.
2007 Aug 1
Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells.
2007 Nov
Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies.
2007 Sep 15
Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells.
2007 Sep 7
Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma.
2008 Aug
Sp1-mediated TRAIL induction in chemosensitization.
2008 Aug 15
Pharmacodynamic assessment of histone deacetylase inhibitors: infrared vibrational spectroscopic imaging of protein acetylation.
2008 Aug 15
Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells.
2008 Dec
Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer.
2008 Dec 15
Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB.
2008 Feb
Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.
2008 Jan 15
Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell.
2008 Jul
A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas.
2008 Jul 15
Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models.
2008 Jun
p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage.
2008 Jun 5
Histone deacetylase inhibitors in lymphoma and solid malignancies.
2008 Mar
Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts.
2008 Mar 15
Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma.
2008 May 15
The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines.
2008 Nov
Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors.
2009
[Effects of histone deacetylase inhibitor MS-275 on expression of survivin and NF-kappaB in the human myeloma cell line U266 cells].
2009 Apr
Lysine acetylation targets protein complexes and co-regulates major cellular functions.
2009 Aug 14
The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes.
2009 Feb
Histone acetylation resulting in resistance to methotrexate in choroid plexus cells.
2009 Feb
Determination of a benzamide histone deacetylase inhibitor, MS-275, in human plasma by liquid chromatography with mass-spectrometric detection.
2009 Jan 15
DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.
2009 Jul
Reactivation of death receptor 4 (DR4) expression sensitizes medulloblastoma cell lines to TRAIL.
2009 Jul
Clinical studies of histone deacetylase inhibitors.
2009 Jun 15
Epigenetic modifiers: basic understanding and clinical development.
2009 Jun 15
"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence.
2009 Jun 2
Rescue of major histocompatibility-DR surface expression in retinoblastoma-defective, non-small cell lung carcinoma cells by the MS-275 histone deacetylase inhibitor.
2009 Mar
[MS-275, a histone deacetylase inhibitor, induces apoptosis and alters survivin gene expression in human myeloma cell line U266].
2009 May
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes.
2009 May
Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.
2009 May
Histone deacetylase inhibitors promote apoptosis and senescence in human mesenchymal stem cells.
2009 May
Three epigenetic drugs up-regulate homeobox gene Rhox5 in cancer cells through overlapping and distinct molecular mechanisms.
2009 Nov
HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression.
2009 Nov 1
Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models.
2009 Oct
MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation.
2009 Oct 15
Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle.
2009 Sep
Antidepressant actions of histone deacetylase inhibitors.
2009 Sep 16
Anti-leukemia activity of MS-275 histone deacetylase inhibitor implicates 4-1BBL/4-1BB immunomodulatory functions.
2009 Sep 17
HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines.
2009 Sep 18
Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies.
2009 Sep 24
Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8.
2009 Sep 3
MS275 enhances cytotoxicity induced by 5-fluorouracil in the colorectal cancer cells.
2010 Feb 10
Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation.
2010 Jan 7
Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells.
2010 Nov-Dec
Patents

Sample Use Guides

Phase I trial data have shown that daily dosing of entinostat is not tolerated. Administration of the drug every 2 weeks or weekly at doses of ≤10 mg/m2 was much better tolerated than daily dosing. The recommended phase II dose for entinostat is 4 mg/ m2 once weekly (solid tumors).
Route of Administration: Oral
Entinostat (MS-275) exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations (e.g., 1 uM) and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations (e.g., 5 uM).
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:58:49 GMT 2023
Edited
by admin
on Fri Dec 15 15:58:49 GMT 2023
Record UNII
1ZNY4FKK9H
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ENTINOSTAT
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
Entinostat [WHO-DD]
Common Name English
ENTINOSTAT [USAN]
Common Name English
MS-27-275
Code English
Pyridin-3-ylmethyl ({4-[(2-aminophenyl)carbamoyl]phenyl}methyl)carbamate
Systematic Name English
CARBAMIC ACID, N-((4-(((2-AMINOPHENYL)AMINO)CARBONYL)PHENYL)METHYL)-, 3- PYRIDINYLMETHYL ESTER
Common Name English
entinostat [INN]
Common Name English
MS-275-27
Code English
ENTINOSTAT [JAN]
Common Name English
SNDX-275
Code English
Classification Tree Code System Code
EU-Orphan Drug EU/3/10/732
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
NCI_THESAURUS C1946
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
Code System Code Type Description
CAS
209783-80-2
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
PUBCHEM
4261
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
DRUG BANK
DB11841
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
WIKIPEDIA
ENTINOSTAT
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
SMS_ID
100000126009
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
EPA CompTox
DTXSID0041068
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
NCI_THESAURUS
C1863
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
CAS
442532-99-2
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
SUPERSEDED
INN
9016
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
USAN
TT-136
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
EVMPD
SUB33300
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
NSC
706995
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
ChEMBL
CHEMBL27759
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
FDA UNII
1ZNY4FKK9H
Created by admin on Fri Dec 15 15:58:49 GMT 2023 , Edited by admin on Fri Dec 15 15:58:49 GMT 2023
PRIMARY
Related Record Type Details
TARGET->WEAK INHIBITOR
Enzymatic Inhibition
IC50
TARGET->WEAK INHIBITOR
Strongly inhibits HDAC3 in cell-free assays. Phase 3.
INHIBITOR
IC50
TARGET -> INHIBITOR
Enzymatic Inhibition
IC50
TARGET -> INHIBITOR
Enzymatic Inhibition
IC50
TARGET -> INHIBITOR
Strongly inhibits HDAC1 in cell-free assays. Phase 3.
INHIBITOR
IC50
TARGET -> INHIBITOR
Enzymatic Inhibition
IC50
TARGET -> INHIBITOR
Enzymatic Inhibition
IC50
TARGET -> INHIBITOR
Enzymatic Inhibition
IC50
Related Record Type Details
ACTIVE MOIETY